The polycystic ovary syndrome (PCOS) is a major health problem that affects approximately 6% of women of reproductive age. PCOS is characterized by hyperandogenism and anovulation, and is the leading cause of female infertility in the United States. Evidence suggests that insulin resistance accompanies by compensatory hyperinsulinemia is a common features of PCOS, and that hyperinsulinemia is responsible in part for the hyperandrogenism of the disorder. However, clinical studies have not assessed the possible role of hyperinsulinemia in promoting the chronic anovulation of PCOS, nor have they examined whether improving insulin selectivity alters PCOS-associated morbidities that may also be linked to insulin resistance and/or hyperinsulinemia, such as glucose intolerance, hypertension, dyslipidemia and atherosclerosis. Therefore, we propose 1) to assess the effects of chronic (12 month) insulin reduction on the hormonal, metabolic (glucose tolerance, blood pressure, lipids, PAI-1, tPA antigen) and ovulatory profiles of women with PCOS, as well as the time course of any changes, 2) to determine whether pharmacologically improving the insulin sensitivity of clomiphene-resistant PCOS women increase the rates of spontaneous and/or clomiphene-induced ovulation, and 3) to determine whether hyperinsulinemia alters 24 hours before and after administration of clomiphene plus placebo or metformin). If our studies confirm an important role of hyperinsulinemia in the pathogenesis of PCOS, they have significant practical implications. That is, they will provide compelling evidence that the first-line treatment of anovulation due to PCOS should be measured aimed at improving insulin sensitivity and reducing serum insulin--including the use of "insulin-sensitizing" agents. Moreover, they will suggest that in women who have failed standard ovulation induction measures, the relatively inexpensive and non-invasive technique of "insulin sensitization" should be employed prior to the initiation of expensive and more complicated technology. Finally, our findings should reveal whether insulin sensitization beneficially affects PCOS co-morbidities that may also be related to insulin resistance or hyperinsulinemia.